ABSTRACT Chronic obstructive pulmonary disease (COPD), which encompasses airway obstruction and/or emphysema, is a growing cause of morbidity and mortality in HIV+ individuals in the current era. Pathogenesis of HIV- associated COPD is poorly understood, but shifts in the lung or gut microbiome may play a role. Studies of the lung microbiome have focused primarily on taxonomic characterization of bacterial communities; however, these taxonomic analyses do not capture functional differences in the microbial communities, focus solely on bacteria, and do not identify specific microbes that stimulate the host immune system, thus potentially missing key distinguishing features critical for disease pathogenesis. Our preliminary data demonstrate important differences in inflammation, host and microbial gene expression, and the metabolome in HIV COPD, suggesting a functional impact of the lung microbiome. The role of the gut microbiome, which can shape immune events in the lung, has also not been investigated in HIV COPD, but given the dysbiosis found in the gut in HIV and relationship of the gut microbiome to inflammation, it may also play a role in HIV COPD. Our overall hypothesis is that functional dysbiosis in HIV+ individuals alters host homeostasis contributing to COPD. Our primary aims are: (1) To characterize associations between functional profiles of microbes and host in the lung in HIV and COPD. We will utilize our ongoing Lung HIV Research Cohort to examine lung microbial and transcriptomic signatures that identify COPD in HIV and test specific causal pathways identified in a validation cohort. We will also analyze stool samples to determine relationship of the gut microbial community to lung function and inflammation in HIV. (2) To test the hypothesis that bacteria recognized by the host differ in HIV+ individuals with COPD compared to those with normal lung function and that these bacteria provoke a heightened inflammatory response. As taxonomic surveys do not differentiate bacteria that are provoking an immune response from those that are merely innocent bystanders, we will then employ cell- sorting of immunoglobulin (Ig)-bound lung bacteria as a novel method to identify members of the bacterial community recognized by the host. We will investigate the effects of these bacteria on lung cell gene expression and inflammation as well as the ability of therapeutic agents such as anti-IL6 receptor antibodies to block bacterial-induced inflammation. (3) To examine longitudinal changes in the lung and gut microbiome in a non-human primate model of HIV and COPD. Studies of COPD are also limited by investigation after development of disease, and we will utilize a non-human primate model to perform a longitudinal study of the impact of lung and gut microbiota on COPD development. These studies will improve our understanding of HIV-associated COPD and will test novel treatment modalities. This project will leverage existing resources to fill gaps in knowledge about the role of the microbiome in HIV-associated COPD, identify novel biomarkers of lung disease, and test new therapeutics.